BackgroundBrain injury is a serious problem in patients who survive out-of-hospital cardiac arrest (OHCA). Neuroprotective drugs could reduce hypoxic-ischemic reperfusion injury. The aim of this... Show moreBackgroundBrain injury is a serious problem in patients who survive out-of-hospital cardiac arrest (OHCA). Neuroprotective drugs could reduce hypoxic-ischemic reperfusion injury. The aim of this study was to investigate the safety, tolerability, and pharmacokinetics (PK) of 2-iminobiotin (2-IB), a selective inhibitor of neuronal nitric oxide synthase. MethodsSingle-center, open-label dose-escalation study in adult OHCA patients, investigating three 2-IB dosing schedules (targeting an AUC(0-24h) of 600-1,200 ng*h/m in cohort A, of 2,100-3,300 ng*h/mL in cohort B, and 7,200-8,400 of ng*h/mL in cohort C). Safety was investigated by monitoring vital signs until 15 min after study drug administration and adverse events up to 30 days after admission. Blood sampling for PK analysis was performed. Brain biomarkers and patient outcomes were collected 30 days after OHCA. ResultsA total of 21 patients was included, eight in cohort A and B and five in cohort C. No changes in vital signs were observed, and no adverse events related to 2-IB were reported. A two-compartment PK model described data the best. Exposure in group A (dosed on bodyweight) was three times higher than targeted (median AUC(0-24h) 2,398 ng*h/mL). Renal function was an important covariate; therefore, in cohort B, dosing was performed on eGFR on admission. In cohort B and C, the targeted exposure was met (median AUC(0-24h) 2,917 and 7,323 ng*h/mL, respectively). ConclusionThe administration of 2-IB to adults after OHCA is feasible and safe. PK can be well predicted with correction for renal function on admission. Efficacy studies with 2-IB after OHCA are needed. Show less
We present the case of a 45-year-old patient who was brought to our emergency department with an out-of-hospital cardiac arrest. The patient arrived 45 minutes after collapse due to ventricular... Show moreWe present the case of a 45-year-old patient who was brought to our emergency department with an out-of-hospital cardiac arrest. The patient arrived 45 minutes after collapse due to ventricular fibrillation. The initial rhythm at arrival to the emergency department was asystole. His laboratory results showed profound lactic acidosis (lactate of 21 mmol/l and pH of 6.6). Time to arrival, rhythm at presentation and the observed lactic acidosis were all interpreted as prognostic signs of a poor outcome but, despite that, it was decided to treat the patient with extracorporeal cardiopulmonary resuscitation (ECPR). Subsequently percutaneous coronary intervention was performed. In contrast to the poor prognosis, the patient was discharged on day 6 with no discernible neurological deficit. This case illustrates that despite biochemical data suggesting profound tissue ischaemia/hypoxia, the outcome of ECPR may be excellent. Such data cannot be reliably used as a single indicator to decide whether or not ECPR should be initiated. Show less
Background: 2-iminobiotin (2-IB) is an investigational neuroprotective agent in development for the reduction of brain cell injury after cerebral hypoxia-ischemia.Objective: The present first-in... Show moreBackground: 2-iminobiotin (2-IB) is an investigational neuroprotective agent in development for the reduction of brain cell injury after cerebral hypoxia-ischemia.Objective: The present first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK) and -dynamics (PD) of 2-IB in healthy male subjects, intravenously infused with or without Captisol (R) as a solubilizing agent.Methods: This randomized, double-blind, placebo-controlled, dose-escalation study was executed in 2 groups of 9 healthy male subjects. A single dose of 2-IB 0.6 mg/kg or placebo was infused over periods between 15 min and 4 h, and repeated doses escalating from 0.6 mg/kg to 12 mg/kg, or placebo were infused every 4 h for 6 administrations in total.Results: Single and multiple doses of 2-IB up to 6 doses of 6 mg/kg with and without Captisol (R) were safe and well-tolerated in healthy male subjects. 2-IB proved to be a high-clearance drug with a volume of distribution slightly exceeding total body water volume, and with linear PK that appeared not to be affected by the presence of Captisol (R).Conclusion: Sulfobutyletherbeta-cyclodextrin (SBECD) in Captisol (R) had a low-clearance profile with a small volume of distribution, with time-independent PK. Preliminary PD characterization of repeated iv dosing of 2-IB in an acute peripheral hypoxic ischemia model in healthy subjects did not reveal any notable effects of 2-IB, noting that this model was not selected to guide efficacy in the currently pursued indication of cerebral hypoxia-ischemia. Show less
This thesis gives insight into the patient group that survived an OHCA and gives directions to the development, evaluation and implementation of integrated rehabilitation treated programs, with the... Show moreThis thesis gives insight into the patient group that survived an OHCA and gives directions to the development, evaluation and implementation of integrated rehabilitation treated programs, with the ultimated goal being that all surviors and their spouses regain optimal quality of life and autonomy. Our studies showed that survivors of an OHCA attending a rehabilitation program may experience cognitive problems. A first attempt of identifying cognitive problems with a set of cognitive screening instruments in patients who attend a (cardiac) rehabilitation program appeared to be feasible, although the screening needs further refinement. The finding that cognitive impairments have a negative effect on exercise capacity is important to take into account while further optimising the best rehabilitation program. Finally, the rehabilitation program should not only focus on the patient but also on the spouse or the caregiver. By developing a core outcome set for rehabilitation the effectivenss of cognitive rehabilitation in OHCA patients and their relatives can be better evaluated. Show less
Schwarzl, M.; Steendijk, P.; Huber, S.; Truschnig-Wilders, M.; Obermayer-Pietsch, B.; Maechler, H.; ... ; Post, H. 2011
